Methods and apparatus for measuring analytes using large scale FET arrays

• US 8,264,014 B2
• Filed: 02/02/2011
• Issued: 09/11/2012
• Est. Priority Date: 12/14/2006
• Status: Active Grant

• Current Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Original Assignee: Life Technologies Corporation (Thermo Fisher Scientific Incorporated)
• Inventors: Rothberg, Jonathan M., Hinz, Wolfgang, Johnson, Kim L., Bustillo, James
• Primary Examiner(s): Le, Thao
• Assistant Examiner(s): GORDON, MATTHEW E
• Application Number:
  US13/019,463
• Publication Number:
  US 20120129728A1
• Time in Patent Office: 587 Days
• Field of Search: 257/253, 257/E23.08, 438/10
• US Class Current: 257/253
• CPC Class Codes: C12Q 1/6818 involving interaction of two or more labels, e.g. resonant energy transfer
• CPC Class Codes: C12Q 1/6874 involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C12Q 2533/101 Primer extension
• CPC Class Codes: C12Q 2565/301 Pyrophosphate (PPi)
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 27/4145 specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
• CPC Class Codes: G01N 27/4148 Integrated circuits therefor, e.g. fabricated by CMOS processing CMOS processing per se H01L21/82
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: H01L 27/088 the components being field-effect transistors with insulated gate
• CPC Class Codes: H01L 29/42324 Gate electrodes for transistors with a floating gate
• CPC Class Codes: H01L 29/78 with field effect produced by an insulated gate H01L29/7725, H01L29/775, H01L29/778 take precedence
• CPC Class Codes: H01L 2924/01006 Carbon [C]
• CPC Class Codes: H01L 2924/01013 Aluminum [Al]
• CPC Class Codes: H01L 2924/01015 Phosphorus [P]
• CPC Class Codes: H01L 2924/01073 Tantalum [Ta]
• CPC Class Codes: H01L 2924/14 Integrated circuits
• CPC Class Codes: H01L 2924/1433 Application-specific integrated circuit [ASIC]
• CPC Class Codes: Y10T 436/22 Hydrogen, per se

Abstract

Methods and apparatus relating to very large scale FET arrays for analyte measurements. ChemFET (e.g., ISFET) arrays may be fabricated using conventional CMOS processing techniques based on improved FET pixel and array designs that increase measurement sensitivity and accuracy, and at the same time facilitate significantly small pixel sizes and dense arrays. Improved array control techniques provide for rapid data acquisition from large and dense arrays. Such arrays may be employed to detect a presence and/or concentration changes of various analyte types in a wide variety of chemical and/or biological processes. In one example, chemFET arrays facilitate DNA sequencing techniques based on monitoring changes in hydrogen ion concentration (pH), changes in other analyte concentration, and/or binding events associated with chemical processes relating to DNA synthesis.

Claims

1. An apparatus comprising:

a sensor array of at least 10⁵ sensors, a given sensor in the array of sensors comprising;

a chemFET having a gate dielectric with a characteristic thickness, a floating gate, and a characteristic threshold voltage, wherein the characteristic threshold voltage of the chemFET is affected by trapped charge; and

a transistor coupled to the floating gate of the chemFET, the transistor providing a current path for charge accumulated on the floating gate.

2. The apparatus of claim 1, wherein the floating gate of the chemFET for the given sensor is coupled to a gate terminal of the transistor.

3. The apparatus of claim 1, where the characteristic threshold voltage of the chemFET of the given sensor is similar to the characteristic threshold voltages of chemFETs of other sensors in the sensor array.

4. The apparatus of claim 1, further comprising control circuitry that detects output signals from the sensors, where the output signals are dependent on the respective threshold voltages of chemFETs of the sensors.

5. The apparatus of claim 4, wherein the output signals from the sensors are substantially similar in response.

6. The apparatus of claim 4, wherein the control circuitry further comprises at least one analog-to-digital converter.

7. The apparatus of claim 1, wherein the sensors of the sensor array are substantially similar in sensitivity.

8. The apparatus of claim 1, further comprising an array of reaction chambers coupled to the array of sensors.

9. The apparatus of claim 8, wherein output signals are created in response to the presence of analytes in the reaction chambers.

10. The apparatus of claim 9, wherein the analytes comprise hydrogen ions.

11. The apparatus of claim 9, wherein the analytes comprise byproducts of a chemical reaction.

12. The apparatus of claim 11, wherein the chemical reaction comprises nucleotide incorporation into a sample nucleic acid template.

17. The method of claim 2, wherein the current path is through a second gate dielectric underlying the gate terminal of the transistor.

18. The method of claim 1, wherein at least some of the charge on the floating gate is accumulated during etching of one or more conductors of the floating gate.

13. A chemFET sensor array comprising:

an array of at least 10⁵ sensors, a given sensor in the array of sensors comprising;

a chemFET including a first gate dielectric between a substrate and a floating gate, and having a characteristic threshold voltage affected by trapped charge in the first gate dielectric; and

a transistor including a second gate dielectric between a gate terminal and the substrate, wherein the gate terminal is coupled to the floating gate of the chemFET, and the second gate dielectric has a thickness less than that of the first gate dielectric.

14. The chemFET sensor array of claim 13, where the characteristic threshold voltage of the chemFET of the given sensor in the array is similar to the characteristic threshold voltages of chemFETs of other sensors in the sensor array.

15. The chemFET sensor array of claim 13, further comprising control circuitry that detects output signals from the chemFETs, where the output signals are dependent on the respective threshold voltages of the chemFETs.

16. The chemFET sensor array of claim 15, wherein the output signals are substantially similar in response.